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Missense mutations of the transforming growth factor beta type II receptor in human head and neck squamous carcinoma
L Garrigue-Antar1, T Muñoz-Antonia, S J Antonia
1Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8032, USA.
Abstract:
In this study, we report the occurrence of missense mutations of the transforming growth factor beta (TGF beta) type II receptor gene in two human squamous head and neck carcinoma cell lines. Both mutations are G:C-->C:G transversions, which result in the replacement of a glutamic acid by a glutamine, and of an arginine by a proline residue, respectively. Moreover, both are located at highly conserved sites within the serine-threonine kinase domain. One of the mutants appears to be defective in its autophosphorylation as well as in the transphosphorylation of the TGF beta type 1 receptor protein, whereas the second mutant appears to be constitutively activated. These are the first reported naturally occurring nucleotide substitution mutations in the T beta R-11 gene in human head and neck cancer cells, which may explain their resistance to TGF beta 1-mediated cell cycle arrest.
Insights
Missense mutations in the transforming growth factor beta (TGF beta) type II receptor gene were found in human head and neck cancer cells. These genetic alterations may cause resistance to TGF beta 1, impacting cell cycle arrest.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Head and neck squamous cell carcinoma (HNSCC) is a significant global health concern.
- Transforming growth factor beta (TGF beta) signaling is crucial for regulating cell proliferation and differentiation.
- Dysregulation of TGF beta signaling is implicated in cancer development and progression.
Purpose of the Study:
- To identify mutations in the TGF beta type II receptor gene (T beta R-II) in human HNSCC cell lines.
- To investigate the functional consequences of these mutations on TGF beta signaling pathways.
- To explore the potential role of T beta R-II mutations in HNSCC resistance to TGF beta.
Main Methods:
- Sequencing of the T beta R-II gene in two human squamous head and neck carcinoma cell lines.
- Analysis of specific nucleotide substitution mutations (G:C-->C:G transversions).
- Functional assessment of mutant receptor activity, including autophosphorylation and transphosphorylation of TGF beta type 1 receptor.
Main Results:
- Identified two distinct missense mutations in the T beta R-II gene within HNSCC cell lines.
- Mutations occurred at highly conserved serine-threonine kinase domain sites.
- One mutant showed impaired autophosphorylation and transphosphorylation, while the other exhibited constitutive activation.
Conclusions:
- These findings represent the first reported naturally occurring nucleotide substitution mutations in the T beta R-II gene in human head and neck cancer.
- The identified mutations may contribute to the observed resistance of these cancer cells to TGF beta 1-mediated cell cycle arrest.
- Understanding these mutations provides insights into HNSCC pathogenesis and potential therapeutic targets.